The American Association for the Study of Liver Diseases (AASLD) has approved practice guideline for patients with hepatocellular carcinoma (HCC) staging, originally developed by the Barcelona Clinic of Liver Cancer.1 The guidelines recommend that liver transplantation, surgical resection, and local ablation therapy, including percutaneous ethanol injection (PEI) and radiofrequency ablation (RFA), can all be considered as curative treatments for patients in the very early and early stages (stages 0 and A). Patients classified in the intermediate stage (stage B) should be treated by transcatheter arterial chemoemolization (transarterial chemoembolization [TACE]). Sorafenib, a multikinase inhibitor with both anti-angiogenic and antiproliferative properties, has been shown to prolong the median overall survival and the median time to progression (TTP) compared to placebo in two randomized, controlled trials (RCT).2,3 Thus, in the 2010 revision of the AASLD guidelines, it was proposed as the current standard of care (SOC) for patients in advanced-stage (stage C) HCC.
In actual fact, among the 22 recommendations in the AASLD guidelines for the management of HCC, only five (21%) can be categorized as supported by level I evidence, according to evidence-based medicine clinical practice guidelines. These five recommendations supported by level I evidence are: (i) HCC surveillance is recommended in high-risk patients; (ii) comparison between results of PEI and RFA; (iii) benefit of TACE; (iv) effects of sorafenib; and (v) no benefit of tamoxifen, anti-androgens, octreotide, or hepatic artery ligation/embolization. The proportion of level I evidence in this HCC guideline is lower than for AASLD chronic hepatitis B (CHB) practice guideline (28/90, or 31%).1 One reason for this is the acknowledged greater difficulty to conduct RCT for HCC than for CHB. Therefore, only adopting results from RCT is not feasible or practical for HCC management. Instead, information from well-conducted longitudinal outcomes research is important, although this notionally only provides level II evidence.
In this issue of the Journal of Gastroenterology and Hepatology, Kim et al. reported observations on 264 patients with stage B HCC who received TACE. Approximately one-third (n = 97) were free of progressive disease (PD[–]) during the first 6 months after TACE, and only one-eighth (n = 33) were PD(–) after a mean 18-month follow up.4 Although TACE is the only recommended treatment in AASLD guidelines for stage B patients, its efficacy remains unsatisfactory. We need more optimal treatment for patients with stage B HCC. In particular, we need to know whether cross-stage or combination use of existing treatment modalities can improve clinical outcomes.
The first issue is whether curative treatment could be used in the management for stage B patients. Conservative Milan criteria and expanded University of California, San Francisco (UCSF) criteria are the two most widely accepted indications for liver transplantation for patients with HCC.5 Some cases of stage B HCC might meet UCSF criteria and undergo liver transplantation. Although surgical resection is the treatment of choice for stage 0/A cases, it is impossible to conduct a RCT comparing this traditional treatment and placebo. The same argument applies to stage B patients. Several clinical outcome studies, including our own,6 have provided evidence of benefit from surgical resection for stage B patients. In particular, such studies provide undeniable evidence that stage B HCC patients selected for surgical resection obtained better survival than those who were treated by TACE. Several recent reviews in surgical literature also showed a better overall survival in cases with surgical resection than in those treated by non-surgical therapies, even though these patients were beyond stage 0/A7. However, surgical resection should not be the ordinary choice to treat stage B patients, as its application is limited to several factors. These include patients’ choice, liver functional reserve, skillful surgeons, and experienced hospitals for postoperative care.
Treating multiple nodular HCC patients with nodule numbers slightly more than three by RFA can sometimes be feasible.8 A meta-analysis of 10 RCT showed TACE combined with percutaneous ablation therapy, especially PEI, improved overall survival for large HCC.9 Mid-term outcomes of an RCT also showed that RFA combined with TACE was more effective than RFA alone in extending the ablated area; it required fewer treatment sessions and decreased local tumor progression rate for patients with intermediate-sized HCC.10 However, current settings for RFA or for combination treatment of TACE and RFA in the treatment of stage B patients are the same as for surgical resection. Therefore, the indications for the above treatment modalities in stage B patients should be documented in the future guidelines.
However, oral medication can be used more conveniently and widely than either surgical or percutaneous procedures. The only approved molecular target therapeutic agent, sorafenib, is currently recommended as the SOC for patients with stage C HCC. Several RCT have been or are being conducted to prove the benefits of combining sorafenib and SOC for patients with earlier stages.
A phase I trial has clarified possible adverse effects experienced by patients treated with a combination of TACE and sorafenib. The incidence of these is generally comparable with those with sorafenib alone; an exception is grade III thrombocytopenia, which might be more frequently noted in the former group.11 Phase II trials also showed that the combination of sorafenib and drug-eluting bead–TACE in patients with unresectable HCC is safe and well tolerated, with a majority of toxicities related to sorafenib. Preliminary data concerning efficacy are also promising.12 In an interim analysis of a phase III RCT in patients before transplantation, a potential superiority in TTP was disclosed in patients with combined treatment of TACE and sorafenib over TACE alone;13 the final results are anticipated soon. Another phase III RCT conducted in Japan and Korea concluded that sorafenib did not significantly prolong TTP in patients who responded to TACE. The result might have been due to delays in starting sorafenib after TACE and/or a low daily dose of sorafenib.14 Furthermore, two ongoing large-scaled RCT in stage B patients, that is, the Eastern Cooperative Oncology Group 1208 and Sorafenib or Placebo in Combination with Transarterial Chemoembolization for Intermediate-Stage Hepatocellular Carcinoma (SPACE), are currently exploring the benefits of combination therapy.
If the results of the afore-mentioned RCT favor combination treatment, should all patients be treated with a combination of TACE and sorafenib instead of TACE alone? The answer is absolutely “no”. Although TACE is now categorized as a non-curative treatment, some patients can be very well controlled or even cured by it. Thus, we should identify those patients with “TACE refractory” or “TACE failure” and then switch to sorafenib monotherapy, or add this agent to ongoing TACE.
Kim et al. proposed the term “stage progression” (SP),4 which they defined as the development of either vascular invasion or extrahepatic metastasis, or progression from stage B to stage C HCC during the course of TACE treatment. Their conclusion is that SP might be the end-point of TACE, so that cases with SP can be defined as “TACE refractory”. However, on the basis of the AASLD guidelines, stage C should not represent TACE refractory, and it is actually defined as out of the indications of TACE. “SP-free survival” should be the end-point of TACE in current practice. Thus, declaring that SP is representative as TACE refractory must be too late. They also concluded that the development of progression or the need for three sessions of TACE within the first 6 months could be predictive of TACE refractoriness. This finding is closer to the situation of “TACE refractory”.
The above issue has been documented in the 2010 version the Japan Society of Hepatology (JSH) guidelines,8 who clearly defined TACE failure or refractory as: (a) an intrahepatic lesion; (a-i) more than two consecutive incomplete necroses (depositions of lipiodol < 50%) are seen by response evaluation computed tomography (CT) within the treated tumors 4 weeks after adequately-performed TACE; (a-ii) more than two consecutive appearances of a new lesion (recurrence) are seen in the liver by response evaluation CT at 4 weeks after adequately-performed TACE; (b) appearance of vascular invasion; (c) appearance of extrahepatic spread; and (d) tumor marker: continuous elevation of tumor markers, even immediately after TACE. The JSH also gave the following recommendation: as hepatic arterial infusion chemotherapy is not effective for TACE failure patients, molecular-targeted therapy is the first choice of treatment.
Cases with tumor progression, followed by intensive TACE, should switch to sorafenib. Kudo and Ueshima reported 15 cases with complete response by sorafenib,15 and two of 90 cases in their center achieved complete response. In a literature review, more than 10 case reports like this can be found from PubMed. We have also experienced a case with complete response. It is believed that if patients are not suitable for TACE, the treatment modality should be switched to sorafenib. However, the indication of combination therapy of TACE and sorafenib is still controversy now. There was not evidence enough to use the combination therapy in all stage B patients initially as a purpose in preventing TAE refractory/failure. Repeated TACE could give significant survival benefits to metastatic HCC patients with conserved liver function and intrahepatic HCC T3 stage.16 Combination therapy should be considered in patients who can get any benefit from TACE for tumor control. However, TACE still has some serious adverse effects, such as deteriorating liver function and intolerance of post-TACE syndrome. For TACE-refractory cases without any contraindications of combination therapy of TACE and sorafenib, an RCT to compare sorafenib with and without TACE should be conducted to elucidate the difference between switching and adding on. Both overall survival and quality of life should be assessed in these studies.
In summary, the combination treatment of TACE and sorafenib is currently a hot issue. In the future, it could become an option for SOC for stage B HCC cases and might improve patient survival. However, more information from RCT and outcome research, such as the interesting data reported by Kim et al. in this issue,4 is required.
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References
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